The central hypothesis of Project 4 is that expression of IL-16 by airway epithelium modulates asthma severity. The project proposes to correlate the presence of a functional SNP in the IL-16 promoter with asthma severity and IL-16 levels in a population of asthmatics characterized by disease severity. Our hypothesis and aims are supported by the following data. IL-16 is expressed in the epithelium of asthmatics, but not atopic non-asthmatics and IL-16 is released into the BAL following antigen challenge. Administration of IL-16 to OVA sensitized animals before aerosol challenge inhibits the inflammation and airway hyper-reactivity to methacholine. The airway inflammation induced in mice transgenic for IL-13 is reduced by 25 percent in mice doubly transgenic for IL-13 and IL-16, and double Tg+ mice live 33 percent longer. We have identified a SNP in the promoter of IL-16 in 7/20 randomly selected individuals. This polymorphism is associated with a lack of IL-16 promoter activity in response to the Th2 cytokines IL-9 and IL-13. Taken altogether, these data led us to hypothesize that IL-16 is induced in airway epithelium by Th2 cytokines, and its expression and release play an immunomodulatory role in controlling disease severity. We further hypothesize that individuals who express the SNP in the promoter will lack a negative feedback of the Th2 inflammation by lacking epithelial expression of IL-16 in response to the pathogenic Th2 cytokines. They might therefore be prone to develop more severe disease. Our aims will test these hypotheses by identifying the promoter genotype in an asthmatic population characterized by severity and correlating these parameters with each other and their relationship to serum IL-16:IL-9, IL-13 levels.